OUTCOMES OF SARS-COV-2 INFECTION IN PATIENTS WITH CELIAC DISEASE: A MULTICENTER RESEARCH NETWORK STUDY
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ORIGINAL ARTICLE Annals of Gastroenterology (2022) 35, 1-5
Outcomes of SARS-CoV-2 infection in patients with celiac disease:
a multicenter research network study
Yousaf Bashir Hadia, Amir Humza Sohailb, Dhairya A. Lakhanic, Syeda Fatima Naqvia, Justin T. Kupeca,
Asad Perveza
West Virginia University, Morgantown; NYU Langone, Long Island, Mineola, NY, USA
Abstract Background Celiac disease (CD) is associated with an increased risk for respiratory infections and
severe outcomes. No data have been reported in the scientific literature regarding the outcomes of
COVID-19 in this population. The aim of this study was to report matched clinical outcomes in a
large cohort of 930 patients with COVID-19 in the setting of known CD.
Methods Analysis of a multicenter research network TriNETX was performed, including
COVID-19 patients aged more than 16 years. Outcomes of COVID-19-positive patients with
concurrent CD were compared with a propensity-matched cohort of patients without CD.
Results A total of 341,499 patients with SARS-CoV-2 infection were identified on the research
network: 930 (0.27%) with CD and 340,569 (99.73%) without CD. In the 30- and 60-day periods
post SARS-CoV-2 infection, 12 (1.29%) and 13 (1.40%) deaths, respectively, were reported in the
CD group. Fewer patients in the CD group reached the composite outcome of either mechanical
ventilation or mortality at 60 days (risk ratio 0.58, 95% confidence interval 0.36-0.95). After
propensity matching, no difference in clinical outcomes was observed.
Conclusion Our data suggest that patients with CD are not at increased risk of COVID-19-related
morbidity or mortality.
Keywords SARS-CoV-2, COVID-19, celiac disease, morbidity, mortality
Ann Gastroenterol 2022; 35 (X): 1-5
Introduction
in other immune-mediated conditions, such as inflammatory
bowel disease [7]. In theory, this intrinsically high susceptibility,
Celiac disease (CD) is a chronic immune-mediated gluten- compounded with malnutrition and immunosuppressive medical
dependent enteropathy, with a global prevalence of 1.4% based on management, may put CD patients at risk of life-threatening
serologic testing and 0.7% based on biopsy results [1]. It is associated disease in the SARS-CoV-2 pandemic [8].
with an increased risk for sepsis, respiratory infections and severe As the SARS-CoV-2 pandemic evolves, it is paramount that
outcomes with conditions such as pneumococcal disease [2], outcomes in commonly susceptible patient subpopulations be
varicella zoster [3], and influenza [4,5]. There is some evidence to studied to allow risk stratification and guide therapy. However, there is
suggest that this increased risk persists even among asymptomatic a paucity of scientific evidence regarding the outcomes of COVID-19
patients after adoption of a gluten-free diet [4,6]. Interestingly, in patients with CD. To address this gap, we analyzed the clinical
this increased susceptibility results from the pathophysiology outcomes among a large cohort of 930 patients with COVID-19 in the
of CD, rather than from immunosuppressive therapy, as seen setting of known CD. Outcomes were compared with a propensity-
matched cohort of COVID-19 patients without CD.
a
Department of Medicine, West Virginia University, Morgantown
(Yousaf Bashir Hadi, Syeda Fatima Naqvi, Justin T. Kupec, Asad
Pervez); bDepartment of Surgery, NYU Langone, Long Island, Mineola,
NY (Amir Humza Sohail); cDepartment of Radiology, West Virginia Patients and methods
University, Morgantown (Dhairya A. Lakhani), USA
Conflict of Interest: None Data source
Correspondence to: Amir H. Sohail, MD, MSc, Department of Surgery,
NYU Langone, Long Island, Mineola, 11501, USA, e-mail: amir.sohail@ A retrospective cohort study was conducted utilizing the multi-
nyulangone.org institutional research network TriNETX (Cambridge, MA, USA)
platform. TriNETX is a federated research network that includes
Received 9 July 2021; accepted 15 November 2021;
more than 40 healthcare organizations in the USA, providing
published online 2 February 2022
real-time access to the healthcare records. It includes >40 million
DOI: https://doi.org/10.20524/aog.2022.0691 patients from the healthcare organizations, in a de-identified
© 2022 Hellenic Society of Gastroenterology www.annalsgastro.gr2 Y.B. Hadi et al
fashion. The data are directly retrieved from the electronic Time windows: Study outcomes were assessed at 30 and 60 days
health record management systems (EHRs) of participating from the index event and included the day of the index event.
organizations. These organizations are large academic centers that Baseline characteristics for patients were considered until the day
operate both tertiary care and satellite outpatient office locations. of COVID-19 diagnosis or first positive COVID-19 test result.
Clinical variables (facts) are derived directly through a built-
in natural language processing system that extracts variables from Statistical analysis
clinical documents. Robust quality assurance is achieved at the time
of extraction from EHRs before inclusion in this database. This The TriNetX platform was used to conduct all analyses.
interface only provides aggregate counts and statistical summaries The chi-square test and t-test were used for univariate analyses.
to protect personal health information and ensures data remain Propensity score matching was performed 1:1 with age,
de-identified at all levels of retrieval and dissemination. race, diabetes, hypertension, chronic lung diseases, nicotine
TriNetX has received a waiver from Western IRB as it only dependence, heart failure, ischemic heart disease, body mass
provides de-identified information. At our institution West index, and sex as covariates, and a propensity score-matched
Virginia University Clinical and Translational Science Institute control group of patients without CD was identified. The 1:1
(WVU CTSI) manages the TriNetX platform and provides matching was performed based on the propensity scores generated
access to the end-users. by using greedy nearest neighbor algorithms with a caliper width
of 0.1 pooled standard deviations; further details are illustrated in
Supplementary Table 1. The balance on covariates was assessed
Patient selection using the standardized mean difference, and absolute values >0.1
were considered positive for residual imbalance. A 2-sided alpha of
Centers for Disease Control and Prevention COVID-19 less than 0.05 was defined a priori for statistical significance. Risk
coding guidance was used to identify COVID-19 cases. The ratios (RR) with 95% confidence intervals (CI) were calculated
International Classification of Diseases, Ninth Revision and Tenth for all analyses. The TriNetX platform utilizes input matrices of
Revision, Clinical Modification (ICD-10-CM) codes and Logical user identified covariates and conducts logistic regression analysis
Observation Identifiers Names and Codes codes for positive to obtain propensity scores for individual subjects. TriNetX
laboratory tests were used. This search strategy has been used randomizes the order of rows in order to eliminate bias resulting
previously in published data from the TriNetX. The codes are from nearest neighbor algorithms.
illustrated in Supplementary Table 1. A real time search and analysis
was conducted on the TriNetX platform and updated through Results
February 1, 2021, to identify patients aged more than 16 years with
SARS-CoV-2 infection. Patients were then classified into a CD
Study population
cohort and a non-CD cohort, based on a previous diagnosis of CD.
This study method has been validated previously [9,10].
We identified a total of 341,499 patients with SARS-CoV-2
infection on the research network: 930 (0.27%) with CD and
340,569 (99.73%) without CD. Baseline characteristics and
Study duration associated comorbid conditions are presented in Table 1.
Comorbidities, including hypertension, diabetes mellitus and
Enrolment between January 20, 2020, and February 01, 2021 lower respiratory diseases, were more common in patients with
was required for inclusion in the study cohort. January 20, 2020, was CD, as was Caucasian race and female sex (all PTable 1 Comparison of baseline clinical characteristics in COVID-19 patients with and without celiac disease (CD) before and after propensity score matching
Variable Before matching After matching
CD cohort (n=930) Non-CD cohort P-value Standard CD cohort (n=930) Non-CD cohort (n=930) P-value Standard
(n=340,569) difference difference
Number Percentage Number Percentage Number Percentage Number Percentage
or SD or SD or SD or SD
Demographics
Age (mean) 46.50 SD: 18.10 45.90 SD: 19.00 0.32 0.03 46.50 SD: 18.10 46.70 SD: 18.10 0.79 0.01
Male 230 24.73% 151,851 44.59% 0.001 0.43 230 24.73% 227 24.41% 0.87 0.01
Female 700 75.27% 187,410 55.03% 0.001 0.43 700 75.27% 701 75.38% 0.95 0.01
Body mass index ≥30 kg/m2 263 28.28% 58,170 17.08% 0.001 0.27 263 28.28% 268 28.82% 0.51 0.01
African American 39 4.19% 60,847 17.87% 0.001 0.45 39 4.19% 46 4.95% 0.43 0.04
Caucasian 808 86.88% 201,013 59.02% 0.001 0.66 808 86.88% 809 86.99% 0.94 0.01
Comorbidities
Hypertension 323 34.73% 90,207 26.49% 0.001 0.18 323 34.73% 326 35.05% 0.88 0.01
Chronic lower respiratory 331 35.59% 52,471 15.41% 0.001 0.48 331 35.59% 340 36.56% 0.66 0.02
diseases 0.04
Diabetes mellitus 179 19.25% 45,712 13.42% 0.002 0.16 179 19.25% 166 17.85% 0.43 0.05
Ischemic heart disease 105 11.29% 26,589 7.81% 0.007 0.12 105 11.29% 92 9.89% 0.32 0.03
Nicotine dependence 97 10.43% 23,478 6.89% 0.002 0.13 97 10.43% 90 9.68% 0.58
SD, standard deviation
Annals of Gastroenterology 34
SARS-CoV-2 and celiac disease 34 Y.B. Hadi et al
1.81) mortality, need for hospitalization (RR 1.00, 95%CI 0.75-
Risk ratio (95%CI)
1.34), critical care requirements (RR 0.89, 95%CI 0.52-1.53), or
0.80 (0.38-1.70)
0.87 (0.42-1.81)
1.00 (0.75-1.34)
0.89 (0.52-1.53)
0.73 (0.38-1.38)
0.70 (0.37-1.31)
1.39 (0.84-2.27)
acute renal failure (RR 1.39, 95%CI 0.84-2.27), as shown in Table 2.
Discussion
Our study shows that patients with CD do not have a
significantly increased risk for worse outcomes, including mortality,
Non-CD cohort (n=930)
Percent
need for hospitalization, critical care services and acute kidney
1.61
1.61
8.71
2.90
2.37
2.47
2.80
After matching
injury. In fact, in the crude analysis, patients with CD were at lower
risk of reaching the composite poor outcome at 60-day follow up
(RR 0.58, 95%CI 0.36-0.95). This association did not hold true
after propensity matching, which may indicate that the lower risk
Number
among CD patients was driven by a higher proportion of females
15
15
81
27
22
23
26
(75.27%) and Caucasians (86.88%) in the CD group, known to have
better outcomes with COVID-19 [8,11]. It is noteworthy that only
10% of patients required hospitalization in the CD cohort. This is
Percent
CD cohort (n=930)
1.29
1.40
8.71
2.58
1.72
1.72
3.87
striking, given the well-documented evidence for worse outcomes
with respiratory infections in CD patients [3,4,12].
As the COVID-19 pandemic continues to evolve, there
Table 2 Clinical outcomes in COVID-19 patients with and without celiac disease (CD) before and after propensity score matching
Number
is a dire need to identify risk factors for poor outcomes with
12
13
81
24
16
16
36
COVID-19 to optimize risk stratification for prevention, vaccine
administration, surveillance and therapeutic measures, especially
in high-risk populations. Evidence on outcomes of COVID-19
Risk ratio (95%CI)
infection shows that patients with a weak immune system,
0.74 (0.42-1.30)
0.70 (0.41-1.21)
1.03 (0.83-1.27)
0.91 (0.61-1.35)
0.62 (0.38-1.01)
0.58 (0.36-0.95)
1.04 (0.75-1.43)
such as the elderly population or those with multiple comorbid
conditions, tend to have a higher case fatality rate [13]. Further,
data show that transplant populations, especially patients on
long-term immunosuppressive therapy, tend to have particularly
worse outcomes with COVID-19 [9,14]. Thus, it could be argued
theoretically that CD, with its baseline alterations in afflicted
Non-CD cohort (n=340,569)
individuals’ immune profile, immunosuppressive therapy, and
Percent
1.75
2.00
8.48
2.84
2.78
2.95
3.74
other well-documented data on higher predisposition and
poor outcomes with respiratory infections (e.g., pneumococcal
Before matching
pneumonia, tuberculosis, and influenza), should alter the disease
course of COVID-19 in the CD population for the worse [2-5].
Interestingly, another postulation is that since the immune-
Number
28,888
10,036
12,742
5,957
6,771
9,662
9,482
mediated cytokine response is primarily responsible for the
damage resulting from COVID-19, CD patients, with their weaker
immune systems, may fare better with COVID-19 infection [15].
Lionetti et al [15] and Zhen et al [16] found no increased
risk for contracting COVID-19 in patients with CD. Likewise,
Percent
CD cohort (n=930)
1.29
1.40
8.71
2.58
1.72
1.72
3.87
Zingone et al conducted a cross-sectional study at the height of
the pandemic in Italy and found that, among a cohort of 138
CD patients, none had been diagnosed with COVID-19 [17].
Number
Data from Sweden also corroborate our findings: Lebwohl
12
13
81
24
16
16
36
et al showed that CD patients with COVID-19 were not at a
significantly higher risk of hospitalization, severe COVID-19 or
all-cause mortality [18]. Importantly, results from the Surveillance
30-day composite outcome
60-day composite outcome
Epidemiology Under Research Exclusion for Celiac Disease
Mortality within 30 days
Mortality within 60 days
(SECURE-CELIAC) [19], an international, de-identified database
comprising 123 COVID-19 cases among patients with CD from 21
CI, confidence interval
Acute renal injury
Inpatient services
countries, also noted comparable hospitalization (12%) and case
Critical care
fatality rates (2.5%) to the general population: 20% hospitalization
rate [20,21] and 1-11% case fatality rate [22,23].
Variable
Our study is one of the first to investigate the outcome of
COVID-19 in patients with CD. Propensity matching and a
Annals of Gastroenterology 34SARS-CoV-2 and celiac disease 5
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Annals of Gastroenterology 34Supplementary material
Supplementary Table 1 ICD 10 and LOINC codes used to identify study participants
LOINC Codes
Number LOINC codes Description
1 94533-7 SARS coronavirus 2 N gene [Presence] in Respiratory specimen by NAA with probe detection
2 94534-5 SARS coronavirus 2 RdRp gene [Presence] in Respiratory specimen by NAA with probe detection
3 41458-1 SARS coronavirus RNA [Presence] in Unspecified specimen by NAA with probe detection
4 94309-2 SARS coronavirus 2 RNA [Presence] in Unspecified specimen by NAA with probe detection
5 94531-1 SARS Coronavirus 2 RNA panel - Respiratory specimen by NAA with probe detection
6 94506-3 SARS coronavirus 2 IgM Ab [Units/volume] in Serum or Plasma by Immunoassay
7 94500-6 SARS coronavirus 2 RNA [Presence] in Respiratory specimen by NAA with probe detection
8 94315-9 SARS coronavirus 2 E gene [Presence] in Unspecified specimen by NAA with probe detection
9 94316-7 SARS-CoV-2 (COVID19) N gene [Presence] in Unspecified specimen by NAA with probe detection
10 94502-2 SARS-related coronavirus RNA [Presence] in Respiratory specimen by NAA with probe detection
ICD 10 codes
1 K 90.0 Celiac disease
2 B34.2 Coronavirus infection, unspecified
3 U07.1 COVID-19, virus identified
4 J12.81 Pneumonia due to SARS-associated coronavirus
5 B97.29 Other coronavirus as the cause of diseases classified elsewhere
ICD code 079.89 (Other specified viral infection) was excluded. This code is mapped to ICD-10 code B34.2 and B97.2, excluded to prevent false positives as it
captures all code for many viral infections
ICD, international classification of diseases; LOINC, logical observation identifiers names and codesYou can also read
